敗血症被定義為因感染而產生的體發炎反應，嚴重者可造成20到50%的死亡率。最近的證據顯示，敗血症的致病病程大致可分為兩個階段。一開始敗血症是身體對入侵的病菌產生無法控制的發炎反應，但隨著時間的增加會慢慢轉變成對抗發炎反應的反應。這導致身體的免疫麻痺現象，且可由單核球表現組織相容性抗原（HLA-DR）的數量減低來反映出來。但為什麼會有這樣的轉變，機轉目前仍然不很清楚。
先前被定義為CD4CD25陽性表現的T淋巴球也就是調節T細胞，被認為對其他淋巴球及吞噬細胞有抑制及調節的作用，而且跟自體免疫、腫瘤免疫、及感染發炎有關。曾經有研究報告指出，CD4CD25陽性表現的T淋巴球在嚴重敗血症及敗血性休克的病人身上會增加。目前認為轉錄因子FOXP3是比CD25更為專一且和調節T細胞的抑制功能較為相關。由此，我們提出一個假說，即較能代表具有功能性調節T細胞的CD4FOXP3陽性T細胞能經由他們的免疫抑制功能而影響嚴重敗血症及敗血性休克病人之預後。我們在南台灣一家醫學中心的內科加護病房進行了一個為期一年的前瞻觀察性研究。本研究總共收集了一十六位健康志願者及一十九位嚴重敗血症或敗血性休克的病人。我們的結果顯示不管是最後存活或死亡的病人其週邊CD4FOXP3陽性T細胞對CD4 T細胞的比例或是其數目在嚴重敗血症或敗血性休克的急性期都會減少。在亞急性期或恢復期，在最後存活的病人其週邊CD4FOXP3陽性T細胞對CD4 T細胞的比例和數目會逐漸恢復至健康人之水準。反之，在最後死亡的病人身上則仍然很低。在調節T細胞的發展和抑制功能上扮演重要角色的TGF-β則和CD4FOXP3陽性T細胞有一致性的結果。從敗血症的急性期到恢復期，它在存活者血清內濃度逐漸增加，在非存活者則逐漸減少。有趣的是，週邊CD4CD25陽性T淋巴球在CD4 T細胞的比例卻與CD4FOXP3陽性T細胞及TGF-β的結果相反。這可能意味著先前認為是自然調節T細胞專一性標誌的CD25可能不是預測嚴重敗血症或敗血性休克預後的適當標誌。我們其他部份的結果則顯示，在非存活病人，其週邊CD4 對CD8 T細胞的比例會逐漸增加，在存活病人則不會。至於週邊第一型及第二型幫助T細胞的比例在病人身上並無太大改變。週邊CD4FOXP3陽性T細胞對CD4 T細胞的比例和CD4 對CD8 T細胞的比例或第一型及第二型幫助T細胞的比例之間並無線性相關性。
我們的結果顯示，對嚴重敗血症或敗血性休克病人而言，週邊CD4FOXP3陽性T細胞對CD4 T細胞的比例或其數目是一個病人預後預測的良好指標。在嚴重敗血症或敗血性休克，調節T細胞可能扮演的是讓無法控制的發炎反應平息的角色。因此，調節T細胞可以預期病人的恢復，而非先前推測的造成免疫麻痺。

Sepsis, defined as systemic inflammatory response syndrome caused by infection, is a potentially lethal disease in acute hospital setting, killing 20 to 50 percent of severely affected patients. Recent evidences showed that there are two stages. Initially, there is an uncontrolled inflammatory response to invading pathogens; however, there is a shift to an anti-inflammatory response over time. The latter results in the immunoparalysis status and is demonstrated by monocyte deactivation with reduced human leukocyte antigen-DR (HLA-DR) expression. The true mechanism of this shift has not yet been clearly elucidated.
Regulatory T cells (Treg), previously characterized by CD4+CD25+, has been recognized to exert a suppression function in T helper lymphocytes and mononuclear phagocytes and play a role in controlling the autoimmunity, tumor immunity and infection inflammation. It has been reported that the number of the peripheral CD4+CD25+ T cells increases in the patient with severe sepsis and septic shock. The role of CD25 as a marker of Treg has recently been replaced by Foxp3, an important transcription factor restricted to the Treg. It has been found that Foxp3 is more specific to the Treg than CD25 and is highly associated with their function. We proposed a hypothesis that CD4+FOXP3+ regulatory T cells, which stood for the functional Treg cells, can influence the outcome of the patients with severe sepsis and septic shock due to their active immunosuppressive function. We performed a one-year prospective observational study in the medical intensive care units in a tertiary teaching hospital in southern Taiwan. Totally, 16 healthy volunteers and 19 patients with severe sepsis and septic shock were recruited in this study. Our results showed that both the percentage of the peripheral CD4+FOXP3+ cells in CD4+ T cells and the absolute number of peripheral CD4+FOXP3+ T cells were depressed at the acute stage of severe sepsis or septic shock in the survival and non-survival patients. In the subacute or recovery stage of the disease course, both the percentage of the peripheral CD4+FOXP3+ cells in CD4+ T cells or the absolute number of peripheral CD4+FOXP3+ T cells recovered gradually in the survival patients. However, this recovery of CD4+FOXP3+ cells was not observed in the non-survival group. TGF-β, which is demonstrated to have a critical role in the development and suppression function of Treg cells, showed a consistent increase with the recovery of the peripheral CD4+FOXP3+ cells in the survival, but not in the non-survival, group. Interestingly, the percentage of the peripheral CD4+CD25+ T cells in CD4+ T cells was in contrary with the results of the CD4+FOXP3+ T cells and TGF-β. This indicates that CD25, previously considered as a specific marker of the natural Treg cell, is not an appropriate marker to predict patient outcome in severe sepsis or septic shock. We also showed that the ratio of peripheral CD4 to CD8 T cells gradually rose in the non-survival patients but stayed stable in the survival patients. Furthermore, the balance of peripheral Th2 cells to Th1 T cells did not change significantly in patients. There was no linear association between the percentage of the peripheral CD4+FOXP3+ cells in CD4+ T cells and the ratio of Th2/Th1 T cells or that of CD4/CD8 in lymphocytes.
Our results showed that the ratio of CD4+FOXP3+ T cells in peripheral CD4+ T cells or the absolute number of peripheral CD4+FOXP3+ cells of the patients with severe sepsis and septic shock is a good predictor of the patients’ outcomes. In severe sepsis or septic shock, Treg may play a beneficial role to reverse the uncontrolled inflammation. The increase of Treg hence may foretell the recovery in these patients, rather than immunoparalysis as previously surmised.

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